Authors :
Ashwini Sri Hari, PhD – University of Utah
Janint Camacho, B.S. – University of Utah
Teresa Musci, B.S. – University of Utah
Philp Moos, PhD – University of Utah
Presenting Author: Cameron Metcalf, PhD – University of Utah
Rationale:
Dravet Syndrome (DS) is a genetic epileptic encephalopathy caused by mutations in the gene SCN1A encoding a voltage-gated sodium channel (Nav1.1) subunit. DS is characterized by pharmacoresistant febrile and spontaneous seizures, behavioral comorbidities, cardiorespiratory changes, and high mortality due to sudden unexpected death in epilepsy (SUDEP). Such pre-existing conditions may make DS patients more susceptible to environmental and other stressors that may exacerbate seizure symptoms and contribute to mortality risk. Rising air pollution levels are a global public health emergency. Carbon monoxide (CO) is a top air pollutant significantly associated with increased seizure risk and epilepsy hospitalizations. Whether ambient exposure to CO would adversely impact seizure, mortality/SUDEP, and morbidity outcomes in DS is unknown. The objective of the current study was to determine if and how sub-chronic CO exposure would affect DS pathophysiology and associated SUDEP risk. Methods:
Young male and female wildtype (WT), and heterozygous (HET) mice (Scn1aA1783V/WT) were divided into 4 experimental groups: WT+Air, HET+Air, WT+CO, HET+CO (N=4/group). All mice were acclimated in the whole-body plethysmography (WBP) and exposure chambers for 5 days. Mice were exposed to room air or 100-300ppm CO for 45mins a day from days 6 through 10 to mimic sub-chronic exposure to ambient CO. Respiratory parameters were assessed prior to exposure on days 6 and 10. After the final exposure on Day 10, a subset of mice underwent the hyperthermia-induced seizure paradigm. Lung, and brainstem were collected from another subset of experimental mice for transcriptomic, and metabolomic analyses. Lipidomic analysis of lung tissue was also performed, and the data is currently being analyzed.
Results:
HETs exposed to CO exhibited a significant (p< 0.0001) decrease in respiratory parameters like minute ventilation and tidal volume compared to HET+Air. Baseline differences were observed in the lung transcriptomes and metabolomes of HETs and WTs. Genes associated with surfactant homeostasis, vascularization, and inflammatory signaling were significantly increased in HET+CO compared to HET+Air. Metabolites like cystathionine, and gluconolactone were significantly (p< 0.05) downregulated and upregulated respectively in the lungs of HET+CO compared to HET+Air. Sub-chronic CO exposure insignificantly altered the temperature threshold for hyperthermia-induced seizures in HETs. However, metabolomic analysis of the brainstem that controls vital autonomic functions showed baseline differences in the metabolomes of HETs and WTs. Metabolites involved in the transsulfuration and pyrimidine nucleotide degradation pathways were significantly (p< 0.05) downregulated in HET+CO compared to HET+Air.